| SCP1 (small C‑terminal domain phosphatase 1) is a member of the DXDX(T/V) family of Mg²⁺‑dependent phosphoserine/phosphothreonine phosphatases that was originally identified as a CTD‑specific phosphatase for the carboxyl‑terminal heptad repeats of RNA polymerase II and later recognized as an evolutionarily conserved regulator of neuronal gene silencing through its control of the RE1‑silencing transcription factor REST. The protein contains the classical DXDX(T/V) catalytic motif embedded in a compact α/β fold that coordinates metal ions and positions substrate phosphoserine or phosphothreonine for nucleophilic attack, and crystal structures of human SCP1 bound to mono‑ and diphosphorylated CTD peptides show a well‑defined active‑site pocket and surrounding hydrophobic and polar contacts that confer preferential recognition and dephosphorylation of phosphoserine‑5 within the Pol II heptad repeat, providing a structural basis for SCP1’s substrate selectivity and its role in transcription initiation checkpoint control. SCP1 dephosphorylates the Pol II CTD to promote transcription initiation and reset polymerase between cycles, but also acts on non‑CTD substrates: biochemical and cellular studies demonstrate that SCP1 specifically dephosphorylates c‑Myc at Ser62, destabilizes c‑Myc, reduces its transcriptional activity and suppresses proliferation of liver cancer cells, and that Ser245 in SCP1’s C‑terminal region is essential for its phosphatase activity toward c‑Myc, identifying SCP1 as a negative regulator of this oncogenic transcription factor and a potential tumor suppressor in hepatocarcinogenesis. SCP1 interacts directly with REST and dephosphorylates the degron region of REST at phosphoserines 861 and 864, stabilizing REST protein and sustaining its scaffold function for neuronal gene silencing complexes that modify chromatin at RE1 elements; knockdown of SCP1 lowers REST levels and increases expression of REST‑repressed neuronal genes such as USP37, BEX1, BDNF and UCHL1, supporting the view that SCP1 is a key modulator of REST‑dependent repression and neuronal differentiation programs. Palmitoylated SCP1 is targeted to the plasma membrane in various cancer cell types, where it negatively regulates angiogenesis, indicating that SCP1 localization is dynamically controlled and that its phosphatase activity influences vascular signaling pathways as well as transcriptional networks. |
